Abstract Human respiratory syncytial virus (RSV) is recognized as the single most important cause of acute respiratory disease in infants and young children worldwide. Elderly populations and immunocompromised individuals are also at significant risk for serious RSV disease. Despite the very substantial disease burden imposed by this virus worldwide, there are no vaccines available. Three interrelated problems have impeded RSV vaccine development. First and foremost is safety. An early formalin-inactivated vaccine (FI-RSV) predisposed infants to more severe disease upon natural exposure to live virus resulting in concerns about the safety of all subsequently developed RSV vaccines, particularly nonreplicating vaccines. Attenuated virus vaccines, which may be effective immunogens, can pose risks in many target populations such as infants and immunocompromised individuals. A second problem is the failure of many vaccine candidates to stimulate protective, long-term immune responses even in model systems, illustrating the lack of knowledge of immune mechanisms required for long-term, protective anti-RSV immune responses. A third significant problem is the failure of most vaccine candidates that have proved to be safe and protective in animal models to stimulate effective immune responses in humans indicating that there are undefined differences in stimulation of humoral anti-RSV responses in model systems and in humans. This proposal is designed to test the hypothesis that novel virus-like particle (VLP) RSV vaccine candidates, unlike any previously tested, may be developed into an effective RSV vaccine. Preliminary results have indicated that these candidates are very effective and safe vaccines in a murine system. The responses of human B cells to these novel vaccine candidates will be explored in a unique system recently developed to study human B cell immune responses, human-mouse xenochimeras. This system will be used to determine requirements for potent stimulation of human B cells by VLPs and RSV. To test the hypothesis, three aims are proposed. Specific Aim 1: to define structural elements in VLPs important for effective humoral immune responses to RSV. Specific Aim 2: to determine the requirements for formation of long-lived plasma cells and memory responses to VLPs and RSV in murine systems. Specific Aim 3: to use human PBL-engrafted humanized NOD scid IL2R&#947;null mice to examine human antibody responses to RSV-VLPs and RSV.